Process for the preparation of substituted octanoyl amides

ABSTRACT

Compounds of formula (XII), are simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the halolactone is reacted with an amine to form a carboxamide, the halogen is replaced with azide, if necessary after the introduction of a hydroxy protecting group, the resulting azide is converted to a lactone, the lactone is amidated and then the azide converted to the amine group, in order to obtain compounds of formula (I) or a salt thereof.

This application is a 371 of PCT/CH01/00400, filed Jun. 26, 2001.

The invention relates to a stereospecific method for the preparation of2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amidesand their physiologically acceptable salts; and new compounds used asintermediates in the multistage process.

In EP-A-0 678 503, δ-amino-γ-hydroxy-ω-aryl-alkanecarbox-amides aredescribed, which exhibit renin-inhibiting properties and could be usedas antihypertensive agents in pharmaceutical preparations. Themanufacturing procedures described are unsatisfactory in terms of thenumber of process steps and yields and are not suitable for anindustrial process. A disadvantage of these processes is also that thetotal yields of pure diastereomers that are obtainable are too small.

It has now been surprisingly found that these alkanecarboxamides can beprepared both in high total yields and in a high degree of purity, andthat selectively pure diastereomers are obtainable, if the double bondof 2,7-dialkyl-8-aryl-4-octenic acid amides is simultaneouslyhalogenated in the 5 position and hydroxylated in the 4 position underlactonization, the lactone ring is opened with an amine during theformation of the carboxamide, then the hydroxy group is replaced withazide, if necessary after protection of the hydroxy group, the resultingcompound is lactonized, the lactone amidated and then the azide groupconverted to the amine group.

A first object of the invention is a process for the preparation ofcompounds of formula I and their physiologically acceptable salts,

wherein

R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₅ isC₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆-alkyl,C₁-C₆alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl,C₁-C₆alkylamino-C₁-C₆-alkyl, C₁-C₆-dialkylamino-C₁-C₆-alkyl,C₁-C₆-alkanoyl-amido-C₁-C₆-alkyl, HO(O)C—C₁-C₆-alkyl,C₁-C₆alkyl-O—(O)C—C₁-C₆alkyl, H₂N—C(O)—C₁-C₆alkyl,C₁-C₆alkyl-HN—C(O)C—C₆alkyl or (C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl,comprising the steps

a) reaction of a compound of formula II,

with an amine of formula R₅—NH₂ to form a compound of formula III,

and

b) reduction of the azide group of the compound of formula III to theamine group and isolation of the compounds of formula I, if necessarywith the addition of a salt-forming acid, comprising the preparation ofthe compound of formula II by reacting

c) a compound of formula IV

wherein X is Cl, Br or I, with an amine to form a carboxamide of formulaV,

wherein R₆ is an amino group,

d1) azidating a compound of formula V to form a compound of formula VI

d2) protecting the hydroxyl group in the compounds of formula V, andazidating the resulting compound of formula VII

wherein S is a protecting group, to form a compound of formula VIII,

e) and then lactonizing the compound of formula VI or VIII in thepresence of an acid to form a compound of formula II.

As an alkyl, R₁ and R₂ may be linear or branched and preferably comprise1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- andt-butyl, pentyl and hexyl.

As a halogenalkyl, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples arefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloro-methyl, 2-chloroethyl and2,2,2-trifluoroethyl.

As an alkoxy, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- andi-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R₁ and R₂ may be linear or branched. The alkoxy grouppreferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkylgroup preferably comprises 1 to 4 C atoms. Examples are methoxymethyl,1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl,methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl,1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl,butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.

As a C₂-C₆alkoxy-C₁-C₆alkyloxy, R₁ and R₂ may be linear or branched. Thealkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms,and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples aremethoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy,1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy,ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy,1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy,propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and1-butyloxyeth-2-yloxy.

In a preferred embodiment, R₁ is methoxy- or ethoxy-C₁-C₄alkyloxy, andR₂ is preferably methoxy or ethoxy. Particularly preferred are compoundsof formula I, wherein R₁ is 1-methoxyprop-3-yloxy and R₂ is methoxy.

As an alkyl, R₃ and R₄ may be linear or branched and preferably comprise1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- andt-butyl, pentyl and hexyl. In a preferred embodiment, R₃ and R₄ incompounds of formula I are in each case isopropyl.

As an alkyl, R₅ may be linear or branched and preferably comprise 1 to 4C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- andi-propyl, n-, i- and t-butyl are preferred.

As a C₁-C₆hydroxyalkyl, R₅ may be linear or branched and preferablycomprise 2 to 6 C atoms. Some examples are 2-hydroxyethy-1-yl,2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or 4-hydroxybut-1-yl,hydroxypentyl and hydroxyhexyl.

As a C₁-C₆alkoxy-C₁-C₆alkyl, R₅ may be linear or branched. The alkoxygroup preferably comprises 1 to 4 C atoms and the alkyl group preferably2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl,2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl,2-ethoxyethy-1-yl, 2-ethoxy-prop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or4-ethoxybut-1-yl.

As a C₁-C₆alkanoyloxy-C₁-C₆alkyl, R₅ may be linear or branched. Thealkanoyloxy group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 2 to 4 C atoms. Some examples are formyloxymethyl,formyloxyethyl, acetyloxy-ethyl, propionyloxyethyl and butyroyloxyethyl.

As a C₁-C₆aminoalkyl, R₅ may be linear or branched and preferablycomprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.

As a C₁-C₆alkylamino-C₁-C₆alkyl and C₁-C₆dialkylamino-C₁-C₆-alkyl, R₅may be linear or branched. The alkylamino group preferably comprisesC₁-C₄alkyl groups and the alkyl group preferably 2 to 4 C atoms. Someexamples are 2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl,2-ethylamino-eth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl,3-dimethylaminoprop-1-yl, 4-methylaminobut-1-yl and4-dimethylaminobut-1-yl.

As a C₁-C₆alkanoylamido-C₁-C₆alkyl, R₅ may be linear or branched. Thealkanoyl group preferably comprises 1 to 4 C atoms and the alkyl grouppreferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl,2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and4-butyroylamidoeth-l-yl.

As a HO(O)C—C₁-C₆-alkyl, R₅ may be linear or branched, and the alkylgroup preferably comprises 2 to 4 C atoms. Some examples arecarboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

As a C₁-C₆-alkyl-O—(O)C—C₁-C₆alkyl, R₅ may be linear or branched, andthe alkyl groups preferably comprise independently of one another 1 to 4C atoms. Some examples are methoxycarbonylmethyl,2-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl,4-methoxycarbonylbut-1-yl, ethoxy-carbonylmethyl,2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonyl-prop-1-yl, and4-ethoxycarbonylbut-1-yl.

As a H₂N—C(O)—C₁-C₆alkyl, R₅ may be linear or branched, and the alkylgroup preferably comprises 2 to 6 C atoms. Some examples arecarbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl,2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1-yl,3-carbamido-2-methylprop-1-yl, 3-carbamido-1,2-dimethylprop-1-yl,3-carbamido-3-methyl-prop-1-yl, 3-dicarbamido-2,2-dimethylprop-1-yl, 2-,3-, 4- or 5-carbamidopent-1-yl, 4-carbamido-3, 3- or-2,2-di-methylbut-1-yl.

As a C₁-C₆alkyl-HN—C(O)—C₁-C₆-alkyl or (C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl,R₅ may be linear or branched, and the NH-alkyl group preferably-comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms.Examples are the carbamidoalkyl groups defined hereinabove, whose N atomis substituted with one or two methyl, ethyl, propyl or butyl.

A preferred subgroup of compounds of formula I is that in which R₁ isC₁-C₄alkoxy or C₁-C₄alkoxy-C₁-C₄alkyloxy, R₂ is C₁-C₄alkoxy, R₃ isC₁-C₄alkyl, R₄ is C₁-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl which ifnecessary is N-monosubstituted or N-di-C₁-C₄alkyl substituted.

A more preferred subgroup of compounds of formula I is that in which R₁is methoxy-C₂-C₄-alkyloxy, R₂ is methoxy or ethoxy, R₃ is C₂-C₄alkyl, R₄is C₂-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl.

An especially preferred compound of formula I is that in which R₁ is3-methoxy-prop-3-yloxy, R₂ is methoxy, R₃ and R₄ are 1-methyleth-1-yl,and R₅ is H₂NC(O)-[C(CH₃)₂]—CH₂—.

As an amino group, R₆ may be —NH₂, primary and preferably secondaryamino, the amino groups comprising 1 to 20 C atoms and preferably 2 to12. The amino group preferably corresponds to the formula —N(R₇)₂,wherein R₇ is C₁-C₄alkyl, cyclopentyl, cyclohexyl, phenyl or benzyl, orboth R₇ are together tetramethylene, pentamethylene or 3-oxapentylene.Preferred examples of R₇ are methyl, ethyl, n-propyl and n-butyl.

Protecting group S in the compounds of formulae VII and VIII arepreferably acyl groups, which may comprise 1 to 12 and preferably 1 to 8C atoms. Some examples are formyl, acetyl, propionyl and butyroyl.Acetyl is especially preferred.

The individual process steps may be carried out in the presence ofsolvent. Suitable solvents are water and organic solvents, especiallypolar organic solvents, which can also be used as mixtures of at leasttwo solvents. Examples of solvents are hydrocarbons (petroleum ether,pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene,xylene), halogenated hydrocarbon (dichloromethane, chloroform,tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether,tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether);carbonic esters and lactones (methyl acetate, ethyl acetate, methylpropionate, valerolactone); N,N-substituted carboxamides and lactams(dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones(acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones(dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols(methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol,hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl ordihydroxy-methyl cyclohexane, benzyl alcohol, ethylene glycol,diethylene glycol, propanediol, butanediol, ethylene glycol monomethylor monoethyl ether, and diethylene glycol monomethyl or monoethyl ether;nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine,triethyl-amine, tripropylamine and tributylamine, pyridine,N-methyl-pyrrolidine, N-methylpiperazine, N-methylmorpholine) andorganic acids (acetic acid, formic acid).

Process Step a)

The reaction of compounds of formula II with a compound R₅NH₂ by openingof the lactone ring to form compounds of formula III is expedientlycarried out in the presence of alcohols or amines which are capable offorming activated carbonic esters or carboxamides. Such compounds arewell-known. They may be 2-hydroxypyridine, N-hydroxycarboxamides andimides, and carboximides (N-hydroxysuccinimide). Organic solvents areused as solvent, tertiary amines being of advantage, for exampletrimethylamine or triethylamine. The reaction temperature may range forexample from approximately 40° C. to 150° C. and preferably from 50° C.to 120° C.

Process Step b)

Reduction of the azide group to the amine group in the compounds offormula III takes place in a manner known per se (see Chemical Reviews,Vol. 88 (1988), pages 298 to 317), for example using metal hydrides ormore expediently using a catalytic method with hydrogen in the presenceof homogeneous (Wilkinson catalyst) or heterogeneous catalysts, forexample Raney nickel or precious metal catalysts such as platinum orpalladium, if necessary on substrates such as carbon. The hydrogenationcan also be carried out if necessary catalytically under phase transferconditions, for example with ammonium formate as hydrogen donor. It isof advantage to use organic solvents. The reaction temperature may rangefor example from approximately 0° C. to 200° C. and preferably from 10°C. to 100° C. Hydrogenation may be carried out at normal pressure orincreased pressure up to 100 bar, for example, and preferably up to 50bar.

The compounds of formula I may be converted to addition salts in amanner known per se by treatment with monobasic or polybasic, inorganicor organic acids. Hemifumarates are preferred.

Process Step c)

The reaction of the halolactone with an amine to form carboxamide isadvantageously carried out in organic solvents such as halogenatedhydrocarbons (chloroform, dichloromethane). The reaction temperature mayrange for example from approximately −30° C. to 80° C. and preferablyfrom −20° C. to 50° C. The amine is expediently used as a salt, forexample as a halogenide. Dimethyl ammonium chloride is preferably used.The reaction is preferably carried out in the presence of at leastequimolar quantities of an alkyl aluminium halogenide such as dialkylaluminium chloride (dimethyl or diethyl aluminium chloride). Afterhydrolytic treatment, the carboxamide can be isolated by means ofextraction and purified by means of chromatography. Thestereoselectivity is high and the yield can be as much as 70% or more.

Process Step d1)

Halogen X may be directly substituted with azide in the carboxamide offormula V obtained as described in step c). Suitable azidation agentsare for example metal azides, especially alkaline earth metal azides andalkali metal azides, as well as silyl azides. Especially preferredazidation agents are lithium azide, sodium azide and potassium azide.The reaction may be carried out in organic solvents, for exampleN-alkylated lactams such as N-methylpyrrolidone or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU). The reactiontemperature may range for example from approximately 20° C. to 150° C.and preferably from 20° C. to 120° C. It may be expedient to include theuse of phase; transfer catalysts. In the broader sense it isadvantageous to carry out the reaction in the presence of preferably atleast equimolar quantities of a base, especially tertiary amines. Thesetertiary amines may serve at the same time as solvents. The preparationand synthetic use of azides are described for example by E. F. V.Scriven in Chemical Reviews, Vol. 88 (1988), pages 298 to 317. As aresult of secondary reactions due to the absence of the hydroxyl group,the yield in the non-optimized reaction is not very high and may beabout 30% or more.

Process Step d2)

It has therefore proved very advantageous to protect the hydroxyl groupagainst azidation in the compounds of formula VI, preferably with acylgroups. To this end, compounds of formula V are reacted with acylationagents, for example carboxylic acid anhydrides such as acetic acidanhydride or carboxylic acid halogenides such as acetylchloride. Thereaction may be carried out with or without solvents. The reactiontemperature may be −20 to 80° C. The reaction is expediently carried outin the presence of bases, for example tertiary amines. Examples oftertiary amines are trialkylamines (trimethylamine, triethylamine),N-alkylated cyclic amines (N-alkylpyrrolidine), dialkylaminopyridines(dimethylaminopyridine) and pyridine. After hydrolytic treatment, theprotected carboxamide can be isolated by means of extraction andpurified by means of chromatography. The yield is generally more than90%.

Azidation may then be carried out as described in process step d1). Theyields are substantially higher than with direct azidation as describedin process step d1) and are more than 75% in the non-optimized processstep d2)

Process Step e)

Lactonization of compounds of formula VI or VIII to form compounds offormula II is expediently carried out at a temperature of −20 to 100° C.and in the presence of a solvent such as alcohols (methanol, ethanol orpropanol) or hydrocarbons (benzene, toluene or xylene). Inorganic acidsand advantageously organic acids are used, especially mineral acids suchas hydrochloric acid, hydrobromic acid or sulfuric acid, sulfonic acidsand carboxylic acids. The azidolactone of formula II may be isolated forexample by extraction with organic solvents. The desired stereoisomer isalso formed in this step at high yields of up to 90% or more.

Some intermediates prepared using the process according to the inventionare new and represent further objects of the invention.

A further object of the invention is thus a compound of formula IX,

wherein

X is halogen, R₁ and R₂ are, independently of one another, H,C₁-C₆alkyl, C₁-C₆-halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, R₆ is anamino group, and R₈ is a protecting group or hydrogen.

A further object of the invention is a compound of formula IXa,

wherein

R₁ and R₂ are, independently of one another, H, C₂-C₆alkyl,C₁-C₆-halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, R₆ is anamino group, and R₈ is a protecting group or hydrogen.

For residues X, R₁, R₂, R₃, R₄, R₆, and R₈ in compounds of formulae IXand IXa, the embodiments and preferences described hereinbefore apply.

The compounds of formula IV are obtainable by reacting in a first step acompound of formula X,

with a compound of formula IX,

wherein R₁ to R₄ are as defined hereinbefore, including the preferences,Y is Cl, Br or I and Z is Cl, Br or I (Y and Z are preferably Br andespecially Cl), and R₉ is C₁-C₆alkyl, R₁₀ is C₁-C₆-akyl or C₁-C₆alkoxy,or R₉ and R₁₀ are together tetramethylene, pentamethylene,3-oxa-1,5-pentylene or —CH₂CH₂O—C(O)— substituted if necessary withC₁-C₄alkyl, phenyl or benzyl, in the presence of an alkali or alkalineearth metal to form a compound of formula XII,

wherein

R₉ is C₁-C₆alkyl, R₁₀ is C₁-C₆alkyl or C₁-C₆alkoxy, or R₉ and R₁₀together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or—CH₂CH₂O—C(O)— substituted if necessary with C₁-C₄alkyl, phenyl orbenzyl.

As an alkyl, R₉ and R₁₀ in formula XII may be branched and preferablylinear and are preferably C₁-C₄alkyl, for example methyl or ethyl. R₁₀as alkoxy may preferably be linear and is preferably C₁-C₄alkoxy, forexample methoxy or ethoxy. R₉ and R₁₀ together are preferablytetramethylene, —CH₂CH₂—O—C(O)— or —CH(CH₂C₆H₅) CH₂—O—C(O)—.

The coupling of Grignard reagents with alkenyl halogenides in an ethersuch as, for example, tetrahydrofuran or dioxan as solvents in thepresence of catalytic quantities of a soluble metal complex, for examplean iron complex such as iron acetonyl acetate, and in the presence ofmore than equimolar quantities of a solvent stabilizing the metalcomplex, for example n-methylpyrrolidone, is described by G. Cahiez etal. in Synthesis (1998), pages 1199-1200. The reaction temperature mayfor example be −50 to 80° C., preferably −20 to 50° C. Catalyticquantities may for example be 0.1 to 20% by weight in relation to acompound of formula VII. It is expedient to carry out the reaction sothat initially a compound of formula VI is converted to a Grignardcompound (for example with magnesium) and then adding a solution of acompound of formula VII, metal complex and N-methylpyrrolidone, or viceversa.

It was found to be of advantage when only catalytic quantities of asolvent stabilizing the metal complexes, for examplen-methylpyrrolidone, were used. Catalytic quantities may for example be1 to 10 mol percent, preferably 1 to 5 mol percent, in relation to thecompounds of formula XI or XII.

Compounds of formula X in the form of their racemates or enantiomers areknown or capable of being prepared according to analogous Processes. Forexample, R₁R₂phenylaldehyde may be reacted withR₃diethoxyphosphorylacetic acid ester to form 2-R₃-3-(R₁R₂phenyl)acrylicacid esters, these may then be hydrogenated to form the correspondingpropionic acid esters, the ester group saponified and the carboxylicacid reduced to alcohol, and finally the hydroxyl group substituted withhalogen. Enantiomers are obtainable by separating the racemates of thecarboxylic acids with for example quinine or by enzymatic resolution ofthe racemates of the corresponding carboxylic acid esters. Details aredescribed in the examples. A possible asymmetric synthesis of compoundsof formula VI is described in EP-A-0 678 503.

Compounds of formula XI in the form of their racemates or enantiomersmay be prepared by the reaction of metalled carbonic esters of formulaR₄CH₂COOR (for example lithium isovaleric acid esters) withtrans-1,3-halogenpropene, then halogenation of the resulting carboxylicacid to form the acid halogenide and reaction with a secondary amine.The coupling of metalled carbonic esters with trans-1,3-halogenpropenecan be carried out asymmetrically according to the method described byD. A. Evans in Asymmetric Synthesis, Vol. 3, 1984 (Academic Press Inc.),pages 2-110. Enantiomers are obtainable by separating the racemates ofthe carboxylic acids with for example cinchonidine or by enzymaticseparation of the racemates of the corresponding carbonic esters.

In a second process step, compounds of formula XII are reacted with ahalogenation agent in the presence of water and if necessary an acid toform a compound of formula IV.

Suitable chlorination, bromination and iodination agents are elementalbromine and iodine, in particular N-chloro, N-bromo andN-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromoand N-iodophthalimide and especially chloro, N-bromo andN-iodosuccinimide, as well as tertiary butyl hypochlorite andN-halogenated sulfonamides and sulfonimides, for example chloramine T.It is of advantage to carry out the reaction in organic solvents. Thereaction temperature may range for example from approximately −70° C. toambient temperature and preferably from −30° C. to 10° C. Carboxamidesare advantageously lactonized in the presence of inorganic or organicacids, at least equimolar quantities of water, and reacted in thepresence of water-miscible solvents, for example tetrahydrofuran ordioxane. Suitable acids are for example formic acid, acetic acid,methanesulfonic acid, trifluoroacetic acid, trifluoro-methanesulfonicacid, toluenesulfonic acid, H₂SO₄, H₃PO₄, hydrogen halides, acid ionexchange resins, and acids immobilized on solid carriers. Water isgenerally used in at least equimolar quantities.

With the choice of lactones of formula IV, the compounds of formula I,which per se are complex compounds, can be prepared in a convergent andsimple manner, which is especially true of these enantioselective ordiastereo-selective synthesis. The total yield from all process steps a)to e) may amount to 40% or more, which makes an industrial applicationfeasible.

The following examples explain the invention in more detail.

A) Preparation of Compounds of Formula X

EXAMPLE A1

An agitated solution of 174 g2R-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutan-1-ol [EP 0 678503] and 1.3 l carbon tetrachloride is cooled to 10° C. 393 mltrioctylphosphine is added dropwise, and the reaction solution is thenstirred for 16 hours at ambient temperature. The mixture is completelyconcentrated by evaporation and the residue extracted betweendichloromethane (3×) and water (1×). The combined organic phases aredried over magnesium sulfate, filtered and concentrated by evaporation.The residue is purified by means of flash chromatography (SiO₂ 60F/ethylacetate/hexane 1:9), and title compound A5 is obtained aftercrystallization (hexane at −50° C.) as a white solid (152.3 g, 82%):melting point 51-52° C.; ¹H-NMR (400 MHz, CDCl₃, δ): 1.0 (m, 6H), 1.71(m, 1H), 1.93 (m, 1H), 2.12 (m, 2H), 2.35 (m, 1H), 2.77 (m, 1H), 3.39(s, 3H), 3.40-3.55 (m, 2H), 3.71 (t, 2H), 3.87 (s, 3H), 4.13 (m, 3H),6.65-6.85 (m, 3H) ppm.

B) Preparation of Compounds of Formula XI

EXAMPLE B1

An agitated solution of 24.9 ml diisopropylamine and 240 mltetrahydrofuran is cooled to minus 15° C., and 100 ml 1.6 M n-butyllithium solution (in hexane) is added over a period of 10 minutes. Thesolution is stirred for 30 minutes at −15° C. and then, over a period 30minutes, a solution of 24.1 ml ethyl isovalerate in 80 mltetrahydrofuran is added dropwise. The mixture is stirred for a further5 minutes at −15° C., and then 19.5 g trans-1,3-dichloropropene and 2.4g sodium iodide are added consecutively. The reaction mixture is stirredfor a further 16 hours at ambient temperature, and then 500 ml 10%aqueous ammonium chloride solution is added. The mixture is extractedwith diethyl ether (3×) and the organic phases washed consecutively withwater (1×), 0.1 M sodium thiosulfate solution (1×) and brine (1×). Thecombined organic phases are dried with sodium sulfate and concentratedby evaporation. By means of distillation, title compound B1 is obtainedas a colourless oil (24.8 g, 76%) ¹H-NMR (400 MHz, CDCl₃, δ): 0.95 (m,6H), 1.30 (t, 3H), 1.92 (m, 1H), 2.20-2.40 (m, 3H), 4.20 (m, 2H),5.80-6.10 (m, 2H) ppm.

EXAMPLE B2

A solution of 150.2 g B1, 500 ml ethanol and 500 ml 2N sodium hydroxidesolution is stirred for 18 hours under reflux. The ethanol is evaporatedfrom the reaction mixture, the aqueous solution acidified with 1Nhydrochloric acid and extracted with diethyl ether (3×). The organicphases are dried over magnesium sulfate and concentrated by evaporation.By means of flash chromatography (SiO₂ 60F/dichloromethane/methanol20:1), title compound B2 is obtained from the residue as a slightlyorange oil (83.7 g, 65%): ¹H-NMR (400 MHz, CDCl₃, δ): 1.03 (m, 6H), 1.98(m, 1H), 2.20-2.45 (m, 3H), 5.80-6.10 (m, 2H) ppm.

EXAMPLE B3

Racemate Resolution of Compound B2

5.0 g B2, 5.0 g cinchonidine and 1.98 ml triethylamine are transferredto 150 ml tetrahydrofuran and stirred for 15 minutes under reflux. Theoil bath is removed and the clear solution with a salt of B3 isinoculated with cinchonidine. Agitation is continued for 1 hour atambient temperature and then for another 1 hour under ice cooling. Theprecipitate is filtered off, washed with twice 25 ml ice-cold acetoneand then dried in a vacuum at 50° C. until constant weight is attained.6.16 g (46.3%) of the enriched salt of B3 is obtained with cinchonidine;melting point 149° C. After double recrystallization from acetone, 4.20g (31.6%) of the enriched salt of B3 is obtained with cinchonidine,melting point 155° C. The salt obtained in this way is distributedbetween 250 ml diethyl ether and 50 ml 1N HCl. The aqueous phase isseparated off, the organic phase washed with saturated NaCl solution,dried over MgSO₄ and concentrated by evaporation in a vacuum. 1.58 g(31.6%) of enriched compound B3 is obtained as colourless oil.

EXAMPLE B4

Asymmetric Synthesis of B3

a) A solution of 290 g 4S-benzyl-3-(3-methyl-butyryl)oxazolidin-2-one in0.58 l tetrahydrofuran is cooled to −78° C., and 1.14 l 1 M lithiumhexamethyldisilazide (in tetrahydrofuran) is added dropwise over aperiod of 65 minutes. The mixture is stirred for another hour at −78°C., and a prepared solution of trans-1-chloro-3-iodopropene intetrahydrofuran is then added. The temperature is allowed to increase to0° C. and agitation is continued for a further 20 hours. 500 ml 10%ammonium chloride solution is added to the reaction mixture, which isthen extracted with diethyl ether (2×1 l). The organic phases are washedwith water (1×1 l), dried with sodium sulfate and concentrated byevaporation. By means of flash chromatography (SiO₂ 60F/ethylacetate/hexane 5:1), title compound B5 is obtained from the residue as aslightly orange oil (582 g, 78%): ¹H-NMR (400 MHz, CDCl₃ , δ): 0.85 (m,6H), 2.02(m, 1H), 2.3-2.55 (m, 2H), 2.75 (m, 1H), 3.30 (m, 1H), 3.88(m,1H), 4.18 (m, 2H), 4.70 (m, 1H), 5.80-6.10 (m, 2H), 7.15-7.40 (m, 5H)ppm. Racemate resolution of compound A3 266.1 g sodium iodide is addedto a solution of 184.7 g trans-1,3-dichloropropene in 0.58 ltetrahydrofuran and the mixture stirred for 30 minutes under exclusionof light at ambient temperature. The mixture is filtered until clear andthe filtrate used in the crude state.

b) To a solution of 155 g B4, 1.3 l tetrahydrofuran and 0.44 l water,stirred at 0° C., 315 ml 30% hydrogen peroxide solution is addeddropwise over a period of 15 minutes. 22.1 g lithium hydroxide is addedto the reaction mixture, then the cooling bath is removed and stirringis continued for 5 hours at 0-20° C. The reaction mixture is cooledagain to 0° C., and a solution of 350 g sodium sulfite in 1.4 l water isadded dropwise over a period of 30 minutes. The pH is adjusted to 9.8 bythe addition of sodium hydrogencarbonate. The reaction mixture isfiltered until clear and tetrahydrofuran evaporated from the filtrate.The aqueous solution obtained is washed with dichloromethane (3×3 l).The pH of the aqueous phase is adjusted to 3.0 with aqueous hydrochloricacid and then extracted with dichloromethane (3×2 l). The organic phasesare dried over magnesium sulfate and concentrated by evaporation on arotary evaporator. By means of distillation, title compound B3 isobtained from the residue as a colourless oil. (142 g, 87%). ¹H-NMR (400MHz, CDCl₃, δ): 1.02 (m, 6H), 1.98 (m, 1H), 2.25-2.45 (m, 3H), 5.85-6.10(m, 2H) ppm.

EXAMPLE B4

4.42 ml oxalyl chloride is added to a solution of 4.54 g B3 in 25 mltoluene at ambient temperature. The reaction mixture is agitated for 15minutes at ambient temperature, and then 0.052 ml N,N-dimethylformamideover a period of 1 minute. The reaction mixture is heated to reflux andagitated for 1 hour. The reaction solution is concentrated byevaporation and the residue distilled. Title compound B4 is obtained asa colourless oil. (4.43 g, 88%). ¹H-NMR (400 MHz, CDCl3, δ): 1.02 (d,3H), 1.08 (d, 3H), 2.16 (m, 1H), 2.40 (m, 1H), 2.45 (m, 1H), 2.68(m,1H), 5.80-6.10 (m, 2H) ppm.

EXAMPLE B5

A solution of 1.53 g dimethylamine, 3.66 ml pyridine and 25 mldichloromethane is cooled to 0° C., and then 4.42 g B5 in 25 mldichloromethane is added dropwise at 0 to −10° C. The reaction mixtureis stirred for a further 2 hours at 0° C. and then concentrated byevaporation on the Rotavapor. The residue is distributed between diethylether (2×) and 2N hydrochloric acid (3×), saturated sodiumhydrogencarbonate solution (1×) and saturated saline solution. Theorganic fractions are combined, dried over sodium sulfate andconcentrated. The residue is distilled, and title compound B6 isobtained as a colourless oil. (4.13 g, 89%). [α]²⁵ _(D-)7,3 (c 1,chloroform). ¹H-NMR (400 MHz, CDCl₃, δ): 0.90 (d, 3H), 0.95 (d, 3H),1.92 (m, 1H), 2.20-2.30 (m, 1H), 2.35-2.50 (m, 2H), 2.98 (s,3H), 3.04(s, 3H), 5.80-6.10 (m, 2H) ppm.

EXAMPLE B6

A mixture of 10.7 g magnesium powder and 120 ml tetrahydrofuran isheated to 60° C., and 0.74 ml 1,2-dibromoethane then added over a periodof 2 minutes (visible exothermic reaction). A solution of 34.6 g A1, 4.0ml 1,2-dibromoethane and 320 ml tetrahydrofuran is added dropwise over aperiod of 15 minutes at 62-64° C. The mixture is stirred for another 30minutes under reflux and then cooled down to ambient temperature. Thereaction mixture is filtered under argon until clear and the resultingGrignard solution added dropwise over a period of 10 minutes to asolution of 20.4 g B6, 0.240 ml N-methylpyrrolidone, 0.88 g iron(III)acetylacetonate in 200 ml tetrahydrofuran at −5 to 0° C. The reactionmixture is agitated for a further 15 minutes at 0 to 10° C., and 320 ml2N hydrochloric acid is then added. The mixture is now extracted withdiethyl ether (3×500 ml) and the organic phases washed consecutivelywith water (1×400 ml) and saturated aqueous sodium chloride solution(1×400 ml). The combined organic phases are dried over sodium sulfate,filtered and concentrated on a rotary evaporator. By means of flashchromatography (SiO₂ 60F/diethyl ether/hexane 2:1), title compound B7 isobtained from the residue as a slightly yellowish oil (36.2 g, 81%): TLCR_(t)=0.09 (diethyl ether/hexane 2:1); ¹H-NMR (500 MHz, CDCl₃, c :0.82-0.99 (m, 12H), 1.49 (m, 1H), 1.69 (m, 1H), 1.78-1.98 (m, 3H), 2.10(m, 2H), 2.17-2.41 (m, 5H), 2.92 (s, 3H), 3.0 (s, 3H), 3.37 (s, 3H),3.58 (t, 2H), 3.84 (s, 3H), 4.10 (t, 2H), 5.26-5.34 (m, 1H), 5.36-5.44(m, 1H), 6.64 (m, 2H), 6.78 (d, 1H) ppm.

C) Preparation of Compounds of Formula IV

EXAMPLE C1

Preparation of

3.85 ml water is added to a solution of 34.2 g B7 and 385 mltetrahydrofuran, and the mixture cooled to 0° C. while being stirred.Then 10 times 1.03 ml 42.5% o-phosphoric acid and times 1.5 gN-bromosuccinimide are added alternately every 3 minutes. The reactionmixture is agitated for another 90 minutes at 0° C. and then, over aperiod of 10 minutes, is introduced to 600 ml sodium hydrogen sulfitesolution cooled to 0° C. The mixture is agitated for another minutes at0° C. and then extracted with diethyl ether (1×1 l and 2×0.5 l) Theorganic phases are washed consecutively with 1N hydrochloric acid (1×0.6l), water (1×0.6 l), saturated aqueous sodium hydrogencarbonate solution(1×0.6 l) and brine (1×0.6 l), dried over sodium sulfate andconcentrated by evaporation on a rotary evaporator. By crystallization(diisopropyl ether-hexane 1:2 at −25° C.), title compound C1 is obtainedas a white crystallizate (27.5 g, 72%): Melting point 48-49° C.; TLCR_(t)=0.09 (diethyl ether/hexane 2:1); [α]²⁵ _(D)=44.2 (c 1,chloroform); ¹H-NMR (500 MHz, CDCl₃, δ): 0.85-1.07 (m, 12H), 1.57-1.65(m, 1H), 1.79-2.00 (m, 3H), 2.07-2.27 (m, 6H), 2.62 (m, 1H), 2.75 (dd,1H), 3.37 (s, 3H), 3.59 (t, 2H), 3.86 (s, 3H), 4.02 (m, 1H), 4.12 (t,2H), 4.35 (m, 1H), 6.72 (dd, 1H), 6.75 (d, 1H), 6.81 (d, 1H) ppm.

D) Preparation of Compounds of Formula V

EXAMPLE D1

A mixture of 6.52 g dimethylamine hydrochloride and 400 mldichloromethane is cooled to −4° C., and 44.8 ml diethyl-aluminiumchloride (1.8M in toluene) is added over a period of 10 minutes. Thetemperature is allowed to rise to 20° C., a solution of 20 g C1 in 80 mldichloromethane is added and the mixture stirred for another 18 hours at35° C. The reaction solution is cooled to 0° C. and then stirred in dropby drop to 800 ml 0.5N cold hydrochloric acid. The reaction mixture isextracted with tertiary butyl methyl ether (2×250 ml), and the resultingorganic phases are consecutively washed with water (500 ml) and(concentrated aqueous saline solution (brine, 200 ml). The combinedorganic phases are dried over sodium sulfate, filtered and concentratedby evaporation. By means of flash chromatography (Sio₂ 60F/ethylacetate/hexane 1:1), title compound D1 is obtained from the residue as aslightly yellowish oil (19.0 g, 68%): TLC R_(t)=0.16 (ethylacetate/hexane 1:1); ¹H-NMR (300 MHz, CDCl₃): δ 0.70-0.95 (m, 12H),1.50-1.95 (m, 7H), 2.05 (m, 2H), 2.20 (m, 1H), 2.55-2.80 (m, 3H), 2.90(s, 3H), 3.05 (s, 3H), 3.30 (s, 3H), 3.45 (m, 1H), 3.50 (t, 2H), 3.80(s, 3H), 4.05 (t, 2H), 4.15 (m, 1H), 6.60-6.75 (m, 3H) ppm.

E) Preparation of Compounds of Formula VII

EXAMPLE E1

A solution of 8.30 g D1 in 100 ml dichloromethane is mixed with 1.54 mlpyridine and cooled to 0° C. Then 1.73 ml acetic acid anhydride and0.186 g 4-dimethylaminopyridine are added consecutively and the mixtureis stirred for 18 hours at room temperature. The reaction mixture ispoured onto 300 ml water and extracted with diethyl ether (2×300 ml).The organic phases are washed consecutively with water (300 ml), 5%aqueous sodium hydrogencarbonate solution (100 ml) and brine (100 ml).The combined organic phases are dried over sodium sulfate andconcentrated by evaporation on a rotary evaporator. By means of flashchromatography (SiO₂ 60F/diethyl ether/hexane 1:1), title compound E1 isobtained from the residue as a colourless oil (7.67 g, 92%): TLCR_(t)=0.27 (ethyl acetate/hexane 1:1); ¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00 (m, 12H), 1.65-2.20 (m, 9H), 2.10 (s, 3H), 2.35 (m, 1H),2.50-2.65 (m, 2H), 3.00 (d, 6H), 3.40 (s, 3H), 3.60 (t, 2H), 3.85 (s,3H), 4.15 (t, 2H), 4.10 (m, 1H), 4.70 (m, 1H), 6.70-6.85 (m, 3H) ppm.

F) Preparation of Compounds of Formula VI

EXAMPLE F1

A mixture of 0.10 g D1, 0.024 g sodium azide and 1 ml DMPU is stirredfor 96 hours at 30° C. The reaction mixture is cooled to roomtemperature, 30 ml water added, and extraction carried out using diethylether (2×30 ml). The combined organic phases are washed with water (2×30ml) and brine (1×10 ml), dried over sodium sulfate, filtered andconcentrated by evaporation. By means of flash chromatography (SiO₂60F/ethyl acetate/hexane 1:1), title compound F1 is obtained from theresidue as a colourless oil (27 mg, 29%): TLC R_(t)=0.14 (ethylacetate/hexane 1:1); ¹H-NMR (300 MHz, CDCl₃): δ 0.75-0.90 (m, 12H),1.10-1.95 (m, 7H), 2.05 (m, 2H), 2.45 (d, 2H), 2.55 (d, 1H), 2.70 (m,1H), 2.80-2.95 (m, 1H), 2.95 (s, 3H), 3.05 (s, 3H), 3.20-3.35 (m, 1H),3.30 (s, 3H), 3.50 (t, 2H), 3.80 (s, 3H), 4.05 (t, 2H), 6.60-6.75 (m,3H) ppm.

G) Preparation of Compounds of Formula VIII

EXAMPLE G1

A mixture of 1.17 g E1, 0.392 g lithium azide and 11.7 ml DMPU isstirred for 21 h at 60° C. The reaction mixture is cooled, and water(100 ml) added. Extraction is carried out using tertiary butyl methylether (3×80 ml) and the organic phases are then washed consecutivelywith water (3×100 ml), 5% aqueous sodium hydrogencarbonate solution (100ml) and brine (100 ml). The combined organic phases are dried oversodium sulfate and concentrated by evaporation on a rotary evaporator.By means of flash chromatography (SiO₂ 60F/diethyl ether/hexane 3:1),title compound G1 is obtained from the residue as a colourless oil (0.83g, 76%): TLC R_(t)=0.06 (diethyl ether/hexane 3:1); ¹H-NMR (300 MHz,CDCl₃):-{ }-δ 0.80-1.00 (m, 12H), 1.15-1.20 (m, 1H), 1.40-2.20 (m, 8H),2.05 (s, 3H), 2.40-2.60 (m, 3H), 3.00 (d, 6H), 3.05 (m, 1H), 3.40 (s,3H), 3.60 (t, 2H), 3.90 (s, 3H), 4.15 (t, 2H), 4.75 (m, 1H), 6.70-6.85(m, 3H) ppm.

H) Preparation of Compounds of Formula II

EXAMPLE H1

A mixture of 70 mg F1, 2 ml toluene and 0.16 ml ethyl acetate is stirredfor 4 hours at room temperature. The reaction mixture is cooled to roomtemperature, 5% aqueous sodium hydrogencarbonate solution (25 ml) isadded, and extraction carried out using diethyl ether (2×20 ml). Thecombined organic phases are dried over sodium sulfate and concentratedby evaporation on a rotary evaporator. The dried residue corresponds tocrude title compound H1 (quantitative); TLC R_(t)=0.41 (ethylacetate/hexane 1:1); ¹H-NMR (300 MHz, CDCl₃): δ 0.85-1.10 (m, 12H), 1.40(m, 1H), 1.60-2.25 (m, 8H), 2.45 (m, 1H), 2.60. (m, 2H), 2.95 (m, 1H),3.40 (s, 3H), 3.60 (t, 2H), 3.85 (s, 3H), 4.15. (t, 2H), 4.30 (m, 1H)),6.70-6.85 (m, 3H) ppm.

EXAMPLE H2

A mixture of 55 mg G1, 38 mg p-toluenesulfonic acid hydrate and 1 mlmethyl alcohol is stirred under reflux for 16 hours. The reactionmixture is cooled to room temperature, 5% aqueous sodiumhydrogencarbonate solution (5 ml) is added, and extraction carried outusing diethyl ether (2×10 ml). The combined organic phases are driedover sodium sulfate and concentrated by evaporation on a rotaryevaporator. The dried residue corresponds to crude title compound H1(0.043 g, 93%); TLC R_(t)=0.41 (ethyl acetate/hexane 1:1); ¹H-NMR (300MHz, CDCl₃): δ 0.85-1.10 (m, 12H), 1.40 (m, 1H), 1.60-2.25 (m, 8H), 2.45(m, 1H), 2.60 (m, 2H), 2.95 (m, 1H), 3.40 (s, 3H), 3.60 (t, 2H), 3.85(s, 3H), 4.15 (t, 2H), 4.30 (m, 1H)), 6.70-6.85 (m, 3H) ppm.

J) Preparation of Compounds of Formula III

EXAMPLE J1

Preparation of

A mixture of 59.1 g H1, 41.82 g 3-amino-2,2-dimethylpropionamide, 2.28 g2-hydroxypyridine in 59.1 ml triethylamine is stirred for 16 hours at90° C. Then 33 ml triethylamine is distilled off over a period of 0.5hours, and the residue is agitated for a further 8.5 hours at 90° C. Thecooled reaction mixture is extracted between ethyl acetate (3×500 ml),saturated aqueous sodium hydrogencarbonate solution (1×500 ml) andsaturated sodium chloride solution (1×500 ml). The combined organicphases are dried over 100 g sodium sulfate, filtered and concentrated ona rotary evaporator. The residue is dried and crude title compound F1 isobtained as an oil (78.4 g, quantitative) (HPLC assay: 88.5%): TLCR_(t)=0.13 (ethyl acetate—hexane 4:1); chromatographed sample: TLCR_(t)=0.13 (ethyl acetate/hexane 4:1); ¹H-NMR (500 MHz, CDCl₃, δ):0.85-0.96 (m, 12H), 1.23 (s, 6H), 1.30-1.40 (m, 1H), 1.53-1.80 (m, 5H),1.82-1.93 (m, 1H), 2.06-2.14 (m, 3H), 2.45-2.57 (m, 2H), 2.87-2.92 (m,1H), 3.13 (d, 1H), 3.32-3.52 (m, 3H), 3.36 (s, 3H), 3.59 (t, 2H), 3.84(s, 3H), 4.12 (t, 2H), 5.51 (bs, 1H), 6.01 (bs, 1H), 6.43 (t, 1H), 6.72(dd, 1H), 6.75 (d, 1H), 6.81 (d, 1H) ppm.

K) Hydrogenation of the Azide Group to Form Compounds of Formula I

EXAMPLE K1

Preparation of

78.4 g (HPLC assay: 88.5%) F1 (crude) is hydrogenated for 3 hours in thepresence of 3.92 g Pd/C₅% and 7.2 ml ethanol amine in 700 ml tert-butylmethyl ether at ambient temperature and 3.0 bar. The reaction mixture isfiltered and the catalyst washed with 300 ml tert-butyl methyl ether.The filtrate is washed consecutively with 400 ml 2N NaOH and 400 mlbrine. The aqueous phases are then extracted with tert-butyl methylether (2×400 ml). The combined organic phases are dried over 100 gsodium sulfate and concentrated by evaporation. The residue is mixedwith 7.31 g fumaric acid and dissolved in 200 ml ethanol and filtereduntil clear. The filtrate is concentrated by evaporation to a totalweight of 104 g and dissolved in 1.7 l acetonitrile at 35° C. Theresulting solution is inoculated with 10 mg of title compound(hemifumarate) and agitated for 17 hours at ambient temperature. Thesuspension is cooled to 0° C. and filtered off by suction after 2 hours.The residue is washed with acetonitrile (3×200 ml) and then dried in avacuum at 35° C.—he title compound K1 (hemifumarate) is obtained aswhite crystals (59.5 g, 81% in relation to J1):-{ }-¹H NMR (360 MHz,DMSO-d₆); δ 0.7-0.9 (m, 12H), 1.04 (s, 6H), 1.27 (m, 3H), 1.4-1.8 (m,4H), 1.94 (m, 2H), 2.23 (m, 1H), 2.35 (dd, J=8.4, 8.0 Hz, 1H), 2.45 (m,1H), 3.08 (m, 2H), 3.2-3.5 (m, 2H), 3.24 (s, 3H), 3.47 (t, J=6.4 Hz,2H), 3.74 (s, 3H), 3.97 (t, J=6.4 Hz, 2H), 6.37 (s, 1H), 6.68 (dd,J=8.0, 2.0 Hz, 1H), 6.77 (d, J=6 Hz, 1H), 6.80 (bs, 1H), 6.83 (d, J=8Hz, 1H), 7.13 (bs, 1H), 7.49 (t, J=6 Hz, 1H).

What is claimed is:
 1. Compounds of formula IX,

wherein X is halogen, R₁ and R₂ are, independently of one another, H,C₁-C6alkyl, C₁-C₆halogen-alkyl C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, R₇ is anamino group, and R₉ is a protecting group or hydrogen.
 2. Compounds offormula IXa,

wherein R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, R₇ is anamino group, and R₉ is a protecting group or hydrogen.